The present invention relates to novel cyclic amino acids and a process for the preparation of D and L enantiomers of the novel cyclic amino acids and derivatives thereof which are used to prepare biologically active peptides useful as pharmaceutical agents.
The development of peptides as therapeutic agents has been hindered by the short duration of action and lack of oral activity of this class of compounds. Thus, unnatural amino acids have been used to replace natural amino acids in order to prepare analogs with enhanced potency and metabolic stability. In some cases these analogs were orally active.
Yabe, Y., et al, Chemical Pharmaceutical Bulletin, Volume 24, pages 3149-3157 (1976) disclosed a series of Luteinizing Hormone Releasing Hormone analogs containing various hydrophobic unnatural amino acid replacements at the 3-position with potent biological activity. Nestor, Jr., J. J., et al, Journal of Medicinal Chemistry, Volume 25, pages 795-801 (1982) disclosed a series of Luteinizing Hormone-Releasing Hormone analogs containing various hydrophobic unnatural amino acid replacements at the 6-position with potent biological activity.
U.S. Pat. No. 4,766,109 disclosed a series of hydrophobic peptides having antihypertensive activity. In some cases the peptides contained racemic 3,3-diphenylalanine as the unnatural hydrophobic amino acid.
Hsieh, K-H, et al, Journal of Medicinal Chemistry, 32:898-903 (1989) disclosed a series of angiotensin II analogs in which the phenylalanine at the 8-position was replaced with various unnatural amino acids including racemic 3,3-diphenylalanine. The authors used racemic 3,3-diphenylalanine since they were unable to resolve this amino acid using hog kidney acylase and carboxypeptidase. The octapeptide diastereomeric mixture containing racemic 3,3-diphenylalanine was subsequently separated by countercurrent distribution into the L- and D-diastereomeric peptides. The authors reported that the peptide diastereomer containing L-3,3 diphenylalanine in place of L-phenylalanine at the 8-position produced a twofold increase in activity.
Josien, H., et al, Tetrahedron Letters 32:6447-6550 (1991) disclosed an asymmetric synthesis of L-(+)-3,3-diphenylalanine from a sultam derived glycine imine. However, this asymmetric synthesis requires long reaction times and proceeds in only 46% overall yield and 95% diastereomeric excess.
Copending U.S. patent application Ser. No. 07/828,399 now U.S. Pat. No. 5,198,548 disclosed a process for the preparation of D(-) and L(+)-3,3-diphenylalanine and D(-) and L(+)-substituted 3,3-diphenylalanines and derivatives thereof which are used to prepare biologically active peptides useful as pharmaceutical agents.
Ryaboi, V. I. and Ginzburg, O. F., Zhurnal Organicheskoi Khimii 1:2069-2071 (1965) disclosed the synthesis of xanthhydryl glycine (DL-.alpha.-amino-9H-anthene-9-acetic acid).
The object of the present invention is to prepare conformationally restrained hydrophobic cyclic amino acids. We have surprisingly and unexpectedly found that a series of bridged 3,3-diphenylalanines are useful in preparing various biologically active peptide analogs. Additionally, we have found that this series of bridged 3,3-diphenylalanines can be resolved into the D and L enantiomers using (-)cinchonidine.